Annually in the U.S., of the nearly 5 million individuals who visit a physician for tendon pain, approximately 200,000 individuals elect to have a surgical repair. Injuries to tendons and ligaments are quite common, and the frequency of these injuries is expected to rise as the population ages and continues to remain active. Tendon repair surgeries are especially common in the U.S., including rotator cuff tendons (51,000 per year), the Achilles tendon (44,000 per year), and the patella tendon (42,000 per year).
Long periods of immobilization and rehabilitation are required because healing of fibrous connective tissue, such as tendons and ligaments, is a time consuming process. Immobilization of injured fibrous connective tissue allows for the healing process to initiate, while minimizing movement which could disrupt the healing process and/or re-injure the healing fibrous connective tissue. However, as soon as the healing process provides enough mechanical strength in, and integrity of, the healing fibrous connective tissue, the individual is generally encouraged to “rehabilitate” the tissue. Rehabilitation of healing fibrous connective tissue is generally accomplished by promoting an active range of motion, which is believed to promote better return of tissue function, accelerate tissue healing, and improve quality of the tissue repair. Further, a decrease in the immobilization period of a limb or joint is desired, as even a period of 6-8 weeks of immobilization can lead to muscle atrophy, joint stiffness, tendon adhesions, risk of osteoarthritis, and other complications. Thus, any treatment that can shorten this time period by improving the rate of healing (and, hence the strength of the repaired tissue), will also improve care by allowing the individual to resume activity sooner.
Although current surgical procedures for repair of injured fibrous connective tissue are generally fairly successful, complications including failure of the repair are not uncommon. For example, chronic degenerative rotator cuff tears present a significant challenge to orthopedic surgeons. Due to tissue loss and retraction, the rotator cuff tears can generate excessive tension following primary repair, and cause failure of the primary repair. Primary repairs of large chronic tears can fail up to 38% of the time because of tendon degeneration and muscle atrophy.
Growth and differentiation factors (GDFs) are members of the family of growth factors belonging to the family of bone morphogenetic proteins (BMPs). GDF-5, GDF-6, and GDF-7 (also known as BMP-14, BMP-13, and BMP-12, respectively) are clearly involved in fibrous connective tissue development and healing, as they stimulate production of fibrous connective tissue in vitro and in vivo. For example, GDF-5 knockout mice have shown this growth factor is essential for normal tendon development. GDF-5 deficiency has also been shown to alter the ultrastructure, mechanical properties, and composition of the Achilles tendon, and significantly delay its healing in an injury model. These GDF proteins are closely related to each other, with amino acid homologies of at least between 80 to 86%. Additionally, the amino acid identity between rodent and human GDFs is 97% for GDF5, 99% for GDF6, and 97% for GDF-7.
In vivo experiments of tendon repair have raised concerns regarding dosage of GDF. GDFs are capable of driving the differentiation of a range of cell types, including osteblasts and chondrocytes, in addition to tenocytes. Therefore, application of GDFs in a dosage other than a proper dose range to a tendon repair site, or application of GDF outside a tendon repair site, runs the risk of inducing the formation of unwanted bone and/or cartilage. Islands of cartilage have been seen in preclinical animal models investigating GDF-7, especially at the higher doses used. Thus, while growth factors often exert potent therapeutic activity on tissue, they can also trigger ectopic or unwanted responses from healthy or untargeted tissue. Of particular concern, growth factors such as GDFs, and particularly at high or unextended dosages, are capable of driving ectopic differentiation of joints, tendon, cartilage and bone. Therefore, delivery of these growth factors must employ a minimal effective dosage of growth factor which is tightly restricted to a particular region. Although few techniques have been explored for delivering growth factors (e.g., polymers eluting growth factor) and to satisfy these delivery demands, there remains a lack of success.
Thus, there remains a need for a system for localized delivery and retention of growth factors to a site of fibrous connective tissue to be treated for promoting healing and/or growth of fibrous connective tissues.